Project 1 (Broide) will investigate innate pathways that contribute to airway inflammation and airway remodeling in asthma. This project will focus on increasing our understanding of how a novel innate cell cytokine (Folistatin Like Protein-1 or FSL-1) as well as a novel innate cell population of pro-inflammatory natural helper cells (NHC) (small mononuclear cells that express high levels of Th2 cytokines, but no markers for T cells, NK cells, mononuclear cells, macrophages, mast cells) mediate important aspects of allergen induced airway inflammation and remodeling. Studies will examine how allergen exposure in atopic asthma activates these two novel interconnected innate pathways to promote airway inflammation and remodeling (i.e. activation of natural helper cells to express Th2 cytokines that subsequently activate M2 macrophages to express FSL-1 a pro-inflammatory and pro-remodeling gene with receptors on smooth muscle and blood vessels). The importance of these novel innate pathways to asthma will be examined by studying levels of their expression in asthma compared to healthy controls, as well as in asthmatics challenged with allergen or rhinovirus. In addition we will determine the stimuli that induce their expression, the distribution of receptors that mediate their activation, and the profile of mediators released following their activation that are important to inflammation and remodeling. Finally, although the major focus of this project will be on studying human asthmatics, mouse models will be used to answer mechanistic questions that are not ethical to perform in humans (such as administration of anti-FSL-1 Ab, and adoptive transfer or depletion of NHC). This research project will interact with both Project 2 (Croft), Project 3 (Zuraw) and Core B to gain insight into how allergen and viral triggers of asthma contribute to airway inflammation and remodeling in asthma.